ABSTRACT The extracellular matrix is an essential pre-requisite for neurite growth and axon guidance, yet we know very little about its role in nerve formation and function within the dental craniofacial skeleton (DCS). This is particularly important in areas such as the alveolar complex and periosteum, in which tissues with disparate matrices (bone, ligament, periosteum, and gingiva) are innervated and function as a single unit. Specifically, the extracellular matrix functions to maintain the appropriate balance between neural systems (i.e. sensory vs sympathetic), as well as develop a unified and functional innervation in order to maintain bone homeostasis. Indeed, conditions such as diabetes and inflammation, which are associated with extracellular matrix damage and nerve loss, are also closely linked to the development of oral bone loss and the progression of periodontal disease. Our long-term goal is to understand how manipulation of the diseased matrix, in conditions such as diabetes, can promote proper re-innervation and skeletal health. We hypothesize that within the DCS, the proteins within the extracellular milleu provide a common link between craniofacial bones and their overlying supportive tissues by facilitating both proper axon extension and neurotransmitter function. The goals of this proposal are to (#1) Characterize the extracellular mechanisms underlying rapid neuron extension and osteoclast recruitment in the dental craniofacial skeleton by defining the foundational extracellular support systems at the nerve-DCS interface and how they change during loading-induced tooth movement within the alveolar bone and periodontium. (#2) Identify the contributions of the matricellular protein periostin to nerve growth and function during loading-induced alveolar remodeling using a orthodontic tooth movement system as an in vivo model of neurite sprouting, osteoclast recruitment and bone remodeling. This model maintains the endogenous extracellular matrix and the physiologic relationship between diverse tissue subtypes in the periodontium allowing the impact of ECM changes on nerve growth and their subsequent impact on bone remodeling to be assessed. (#3) Define the role of extracellular matrix glycation and neuropathy on adaptive nerve regeneration and bone remodeling in the diabetic state by first determining what neuropathy looks like in the diabetic periodontium, then separating the impact of two common complications of diabetes, protein glycation and neuropathy, on adaptive nerve regeneration and bone quality in the diabetic state. In summary, this proposal will define key extracellular pathways that modulate the relationship between neurite outgrowth, osteoclast recruitment, and bone remodeling in the alveolar complex thereby advancing our understanding of oral health and disease. In doing so, we hope to identify regulators of rapid neural growth and function within the dental craniofacial skeleton, providing novel therapeutic targets for tissue regeneration.